More than 350 million people are chronically infected with the hepadnavirus Hepatitis B (HBV). The spectrum of the disease is diverse and variable, ranging from an inactive carrier state to progressive chronic hepatitis B (CHB). However, in most HBV carriers, liver disease progresses through cirrhosis to hepatocellular carcinoma, leading to approximately 1 million deaths each year and currently represent 5-10% of cases of liver transplantation. Hence, the goal of drug therapy is to halt the progression of cirrhosis and to block the appearance of cancer. Current approaches for the treatment of Hepatitis B infections include interferon therapy and treatment with nucleoside analogues. Interferon therapy (either standard or pegylated) stimulates the hosts' antiviral immune response. Interferon must be given by parenteral administration and its use is associated with several side effects (such as influenza-like symptoms, anorexia and depression). The main goal of nucleoside analogue therapy is to block viral DNA synthesis and thereby reduce the number of infected hepatocytes. Currently, five nucleoside analogues have been licensed for the treatment of HBV infections. lamivudine (LMV), adefovir dipivoxil (ADV), entecavir, telbivudine, and tenofovir disoproxil fumarate (TDF) (FIG. 1). TFV and ETV are nowadays considered as first-line treatments because of their potent antiviral activity and their high barrier to resistance.

Lamivudine, entecavir and telbivudine are classical antiviral nucleosides, whose antiviral activity depends upon their intracellular metabolism within virus-infected cells to form sequentially the mono-, di- and triphosphates. It is these nucleotides, and especially the triphosphates that are the pharmacologically active species, as they are incorporated into a growing DNA strand by a DNA polymerase, resulting in chain termination or fraudulent DNA/RNA. The first phosphorylation step leading to the formation of the nucleoside 5′-monophosphate is commonly catalyzed by a nucleoside kinase encoded by the host cell or the virus infecting the host cell. Conversion of the nucleoside monophosphate to the corresponding 5′-diphosphate and triphosphates is carried out by nucleoside, nucleotide, and nucleoside diphosphate kinases, respectively. Hence, cellular kinases, as well as virally-encoded kinases play a vital role in the activation of nucleoside drugs.
Adefovir and Tenofovir are both nucleoside phosphonates, which can be considered as nucleoside monophosphate analogues, having the advantage of being metabolically stable, as the phosphorus-carbon bond is not susceptible to hydrolytic cleavage. Moreover, the presence of a phosphonate group allows the first phosphorylation step, required for nucleoside activation to be skipped, therefore bypassing the rate-limiting step in the conversion to the nucleoside-triphosphate. Although metabolically stable, phosphonates are negatively charged at physiological pH, and hence, are not able to penetrate the lipid-rich cell membrane, which hampers their antiviral activity. Therefore, these compounds are marketed as an orally bioavailable prodrug.
In order to bypass the first, rate-limiting phosphorylation step in the bioactivation of nucleosides, cyclic nucleoside phosphonates have been synthesized. An example includes a series of L-2′-deoxythreose nucleoside phosphonate analogues that have been synthesized (see J. Am. Chem. Soc. 2005, 127, 5056-5065). Two congeners showed excellent activity. PMDTA (phosphonomethoxydeoxythreosyl adenine) displayed an EC50 value of 2.53 μM against both HIV-1 and HIV-2, whereas PMDTT (phosphonomethoxydeoxythreosyl thymine) was endowed with an IC50 value of 6.59 μM against HIV-1 and HIV-2. In addition, these analogues lack cellular cytotoxicity (CC50 values are >316 μM for PMDTA and >343 μM for PMDTT). Despite its promising antiviral profile, the highly charged nature of the phosphonate moiety hampers their cellular permeability.
The present invention is based on the unexpected finding that dome prodrugs of these PMDT show unexpected biological properties, in particular have significant antiviral activity against the Hepatitis B virus.